Pharmacokinetics of Novel Dopamine Transporter Inhibitor CE-123 and Modafinil with a Focus on Central Nervous System Distribution

Abstract

S-CE-123, a novel dopamine transporter inhibitor, has emerged as a potential candidate for cognitive enhancement. The objective of this study was to compare the tissue distribution profiles, with a specific focus on central nervous system distribution and metabolism, of S-CE-123 and R-modafinil. To address this objective, a precise liquid chromatography–high resolution mass spectrometry method was developed and partially validated. Neuropharmacokinetic parameters were assessed using the Combinatory Mapping Approach. Our findings reveal distinct differences between the two compounds. Notably, S-CE-123 demonstrates a significantly superior extent of transport across the blood–brain barrier (BBB), with an unbound brain-to-plasma concentration ratio (Kp,uu,brain) of 0.5, compared to R-modafinil’s Kp,uu,brain of 0.1. A similar pattern was observed for the transport across the blood–spinal cord barrier. Concerning the drug transport across cellular membranes, we observed that S-CE-123 primarily localizes in the brain interstitial space, whereas R-modafinil distributes more evenly across both sides of the plasma membrane of the brain’s parenchymal cells (Kp,uu,cell). Furthermore, our study highlights the substantial differences in hepatic metabolic stability, with S-CE-123 having a 9.3-fold faster metabolism compared to R-modafinil. In summary, the combination of improved BBB transport and higher affinity of S-CE-123 to dopamine transporters in comparison to R-modafinil makes S-CE-123 a promising candidate for further testing for the treatment of cognitive decline.

Keywords

• dopamine transporter inhibitor
• <i>S</i>-CE-123
• <i>R</i>-modafinil
• neuropharmacokinetic
• tissue distribution
• metabolism